In concept, the goal of this project is quite simple - to use somatic gene therapy to correct the metabolic defects resulting in the diseases known as type 1 and type 2 diabetes mellitus. These are diseases with some similarities but more differences. The amelioration of their consequences is unlikely to be as simple as transducing the liver to produce insulin. In type 1 diabetes in which insulin deficiency is the major problem, the need for insulin varies several fold during the course of the day. In type 2 diabetes, the defect is not completely understood, but therapy directed only at additional insulin replacement is unlikely to be completely successful. Dr. Woo and his colleagues have planned a series of approaches to address these complex diseases. The project in which I will be involved will add a "suicide gene", that of thymidine kinase, to the molecular construct containing the insulin gene whose expression is driven by a retroviral promotor. This will address directly an obvious problem in gene therapy for type 1 diabetes - the possibility of producing hypoglycemia from excessive expression of the trans gene. This project will provide experience in every aspect from conception to cloning of the relevant gene, packing in virus, and the therapy itself.